Download The Influence of Systemic Medications on Osseointegration of

The Influence of Systemic Medications on
Osseointegration of Dental Implants
Aviv Ouanounou, MSc, DDS, FICO; Siavash Hassanpour, BSc, MSc, DDS; Michael Glogauer, DDS, PhD, Dip Perio
Cite this as: J Can Dent Assoc 2016;82:g7
Abstract
Dental implants are routinely used to treat edentulism. Their success depends
on osseointegration, the direct functional and structural interlocking of
implant and bone. The osseointegration mechanism is similar to bone
remodeling and healing. Thus, chronic use of systemic medications that
can interfere with bone turnover and healing may affect osseointegration,
resulting in premature implant loss. The aim of this narrative review is to
analyze the reported effects of systemic medications on osseointegration.
D
ental implants have been used to treat, routinely and predictably,
partial and complete edentulism in dentistry for the last 30 years.
The clinical success of dental implants depends on osseointegration,
defined by Brånemark as “a direct connection between living bone and
a load-carrying endosseous implant at the light microscope level.”1 The
success rate for dental implants is high, with routine reports of 90–95% success.
Clinical research into implant dentistry has identified peri-surgical acute
infections, surgeon inexperience, lack of initial implant instability, lack of
patient compliance, uncontrolled parafunction, smoking, poor oral hygiene,
uncontrolled diabetes2 and head and neck radiation as factors contributing
to failed osseointegration.3-8 However, there are relatively few absolute
contraindications to implant therapy; they are recent myocardial infarction
and cerebrovascular accident, valvular prosthesis surgery, immunosuppression,
uncontrolled bleeding issues, active treatment of malignancy, drug abuse,
psychiatric illness and intravenous bisphosphonate use.3 Therefore, the vast
majority of the population is considered medically eligible for implant therapy.
A large proportion of the population suffering from chronic conditions are under
medical management that includes long-term use of medications. Yet, relatively little is known about the effects of chronic medication use on the success of
dental implants and osseointegration. Successful osseointegration of dental
implants requires normal functioning of native biological activities that occur
during bone remodeling, the dynamic process of bone resorption by osteoclasts and new bone formation by osteoblasts.9 Thus, any events that can alter
bone repair and bone healing may, in turn, alter successful osseointegration
and ultimately lead to premature implant loss or peri-implant complications.
Although chronic use of multiple systemic medications can affect bone healing
and repair, the potential effects of long-term prescription of such medications
on osseointegration of dental implants have not been adequately investigated.
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In this paper we review the literature on the influence of
several agents on osseointegration, specifically, cyclosporine, glucocorticoids, alcohol, selective serotonin
reuptake inhibitors, non-steroidal anti-inflammatory drugs,
bisphosphonates and chemotherapeutic agents. These
do not represent a comprehensive list of chronically
prescribed medications. Rather they represent some of
those most commonly used chronic medications with
reported physiological, biological and pharmacological effects on bone metabolism that may affect the
bone-to-implant interface and, thus, osseointegration.
Cyclosporine
Cyclosporine A (CsA) is an immunosuppressive drug
prescribed to prevent transplant rejection and to treat
immunologic diseases. Although the exact mechanism
of action of CsA is unclear, it has been shown to have
anti-anabolic effects on osteoblasts and to supresses
and inhibit the critical role of T-lymphocytes in bone
remodeling.10 Animal studies have shown that CsA
administration leads to high bone turnover, resulting in
an imbalance between bone resorption and formation,
leading to osteopenia and enhanced bone loss.11,12
Furthermore, several studies have reported that this
agent may increase the incidence of bone fracture
and may be associated with bone mineral loss.13-15
In relation to implants, several reports have demonstrated the negative effect of CsA on osseointegration.
Sakakura and co-workers10,16 showed that long-term
administration of CsA negatively influences bone healing
around dental implants in rabbits. Durate et al.17 also
showed increased bone remodeling and significant
bone loss in rabbits that were exposed to CsA; the
authors concluded that the administration of CsA may
negatively influence bone healing around titanium
implants. Sakakura and co-workers18 also investigated the
effects of CsA on bone around successfully osseointegrated implants in rabbits. The authors noted that the
administration of CsA in rabbits with previously integrated
dental implants impaired mechanical retention.
There is a lack of clinical evidence of the effects of
CsA on osseointegration of dental implants in humans.
However, studies have shown that patients receiving CsA
after transplant surgery may experience an increased
incidence of osteoporosis.14 The exact mechanism of
action of CsA around bone tissue is not clearly understood.
It has been suggested that CsA-induced alteration of
bone metabolism may be related to its immunosuppressive mechanisms mediated by cytokines.10 Patients
undergoing CsA therapy may not be ideal candidates
for implant therapy because of compromised general
health. Further, considering the effects of CsA on bone
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turnover, the use of this immunosuppressive agent before
and during implant therapy must be carefully considered,
as the prognosis of the implant-supported prosthesis is
directly related to bone density around the implant.19
Glucocorticoids
Glucocorticoids are widely used to suppress inflammation
in chronic diseases, such as asthma, rheumatoid arthritis,
inflammatory bowel disease and autoimmune diseases.20
Bone loss is one of the most common and debilitating side
effects associated with prolonged high-dose glucocorticoid
therapy, and this may negatively affect implant osseointegration.21 Studies have shown that glucocorticoids reduce
bone formation and increase bone resorption,22 and several
have reported a loss of osseointegration associated their
chronic use.23,24 Moreover, chronic use of glucocorticoids
has been cited as an absolute contraindication25 or relative
contraindication in the placement of implants in the jaws.26
However, we found conflicting evidence regarding the
effects of glucocorticoids on osseointegration and implant
healing. For instance, Bencharit et al.27 demonstrated
that once osseointegration has occurred, the long-term
prognosis for the implant is favourable, despite the use
of glucocorticoids. Using male rabbit tibia, Werner and
co-workers28 demonstrated no significant difference in
osseointegration between a group that was injected with
dexamethasone and the control group. Another study26
examined the effects of steroid administration on the
osseointegration of dental implants with the rabbit tibia and
mandible. The authors reported that the “removal torque”
of implants placed in the tibia was reduced with steroid
administration, but this did not apply to implants placed in
the mandible. They concluded that steroid administration
might have less effect on osseointegration of titanium
implants in the mandible than in the skeletal bone.
Glucocorticoids have deleterious effects on bone
remodeling and turnover, as they promote osteoblast
apoptosis and favour the differentiation of bone marrow
cells into adipocytes.21 Together these changes lead to
decreased bone formation, thus shifting the balance
toward bone loss. Unfortunately, the exact effect of these
changes in bone metabolism on successful long-term
osseointegration of dental implants in humans has not
been determined in high-quality clinical studies.
Alcohol
Alcohol is one of the most widely used drugs in the world,
with reported rates of alcoholism as high as 10% in the
North American population.29 Alcohol is a central nervous
system depressant with wide-ranging and detrimental
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systemic effects.30 It has been shown to affect the central
nervous system, gastrointestinal tract, immune system,
liver and cardiovascular system.30 Alcohol also inhibits
osteoclast activity, reduces bone quality and delays
fracture repairs.31,32 Alcohol consumption is a risk factor for
osteoporosis,33 with reductions in cortical bone area and
trabecular volume reported in alcoholic animal models.34
A recent study35 examining bone-to-implant contact
as well as bone formation around titanium implants
in rabbits that were fed an alcoholic diet found that
alcoholic rabbits had significantly less bone density and
reduced direct bone-to-implant contact.35 De Deco
et al.32 found similar results in a rat model system. In a
retrospective study,36 more than half of the patients lost
their implants because of alcohol addiction. A matched
case–control analysis37 found that implant failures clustered
in patients classified as heavy drinkers (more than 5 units
a day) as opposed to light drinkers (less than 5 units a
day) and those who denied alcohol consumption.
Although the exact mechanism by which alcohol alters
bone metabolism is still unclear, it has been suggested that
alcohol intake may alter the ongoing balance between
erosion and remodeling of bone tissue.38 Patients with routine
and excessive alcohol consumption may be at higher risk of
implant failure. These patients have been shown to display
delayed healing following the induction of a surgical wound
as a result of alcohol-induced deficiencies in the complement system (part of the immune system), suppression of
T-lymphocytes and impairment in the mobility, adhesion and
phagocytic capabilities of the innate immune system.39
Selective Serotonin Reuptake Inhibitors
Depression, a globally prevalent disorder,40 is a complex
mental illness that is associated with significant disability
and reduced quality of life. Low levels of serotonin have
been implicated as the cause of depression,41 and, in the
last 3 decades, selective serotonin reuptake inhibitors (SSRIs)
have been used successfully to treat depression. SSRIs
have many advantages, such as ease of dosing and low
toxicity in overdose. Moreover, they have been widely used
because their adverse-effect profile is less prominent than
that of some other antidepressant agents. Also, in contrast
with other antidepressants (e.g., tricyclic antidepressants
and monoamine oxidase inhibitors), these agents do not
appear to affect blood pressure or heart rate. SSRIs have
been recommended as first-line antidepressant medications and this recommendation is supported by the 2011
American Psychiatric Association (APA) guidelines.42-46
Specifically, these drugs inhibit serotonin reuptake from the
synaptic cleft into presynaptic nerve terminals, thereby
increasing the concentration of serotonin in the synaptic
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cleft and enhancing serotonin neurotransmission.47 The
association between depression, bone loss and bone
disease is well documented.48 Depression has been linked
to low bone mass, and SSRIs have been linked to falls,
bone loss and fractures.49 A recent meta-analysis found
SSRI use to be associated with a significantly greater risk
of fractures.50 Moreover, SSRIs, but not tricyclic antidepressants, another widely used medication for the treatment
of depression, were associated with lower bone mineral
density.51 It has been suggested that serotonin receptors
found in osteocytes, osteoblasts and osteoclasts can
be activated by SSRIs and, thus, alter their function.44
Taking all these factors into consideration, Wu et al.52
postulated that treatment with SSRIs may have a negative
effect on dental implant osseointegration. In a retrospective
cohort study of 916 implants in 490 patients, their data
demonstrate that treatment with SSRIs was associated with
an increased risk of failure of osseointegrated implants.
The authors propose that the main factor contributing to
implant failure was problems with mechanical loading
of the implants. They add that this was, in part, a result
of the fact that serotonin played an important role in the
anabolic response of bone to mechanical loading and
conclude that SSRIs may cause bone loss by inhibiting
the bone-remodeling processes triggered by mechanical
loading.52 Based on their results, the authors propose careful
surgical treatment planning for patients taking SSRIs.
Nonsteroidal Anti-Inflammatory Drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) have
anti-inflammatory and analgesic properties and, thus,
are commonly prescribed in the dental setting. This group
of drugs is also routinely used by many patients for the
management of chronical inflammatory conditions, such
as arthritis. A number of NSAIDs, including ibuprofen,
naproxen, flurbiprofen, diflunisal and ketorolac, have
been shown to be effective for dental pain. These agents
are also routinely prescribed as analgesics and anti-inflammatory agents following dental implant surgery.
The mechanism of action of NSAIDs is well known and has
been associated with the enzyme cyclooxygenase (COX).
Specifically, NSAIDs prevent the conversion of arachidonic
acid to prostaglandin. Prostaglandins play an important
role in normal bone healing, osteoclastic activity, bone
formation and angiogenesis.53 However, conflicting information on the effect of these drugs on bone remodeling
has been reported. For instance, several studies show
that healing of bony fractures is delayed when NSAIDs
are used.54,55 Also, Ribeiro and co-workers56 reported a
negative effect of meloxicam on the osseointegration of
titanium implants in rats. They showed a reduction in the
degree of bone-to-implant contact within both cortical and
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cancellous bone. Meloxicam also negatively affects bone
area and bone density when administered subcutaneously
to male rats.57 Similarly, in vivo studies on a male rat tibia
model demonstrated that administration of 1.07 mg/kg
of diclofenac twice daily for 5 days delayed peri-implant
bone healing.58 In addition, Chikazu et al.59examined the
effect of COX-2 on bone healing after the placement
of implants in the femurs of male wild-type (COX-2(+/+))
and knockout (COX-2(−/−)) mice. They concluded that
minimal new bone was formed around the implants
in the COX-2 knockout mice, proving that COX-2 is
essential for proper osseointegration of dental implants.
With respect to humans, a randomized double-blind
control trial demonstrated that oral administration of 600
mg of ibuprofen 4 times daily for 7 days had no significant
effect on loss of bone level after 3 or 6 months.60 A 2014
retrospective study61 examining the causes of osseointegration failure noted that disproportionately more failures
occurred in the cohort of patients who received NSAID
therapy during the period surrounding dental implant
surgery. In addition, the NSAID-treated cohort experienced greater perio-implant bone loss and clustered
implant failures.61 All in all, despite the lack of consensus
in the literature, it may be advisable to avoid prescribing
NSAIDs for the management of post-operative pain and
edema immediately before or after implant placement.
Bisphosphonates
Bisphosphonates are antiresorptive agents that specifically
inhibit osteoclast activity and are, therefore, commonly
used to maintain bone density and strength.62 Oral bisphosphonates, which are more commonly prescribed than
intravenous forms, are given to patients for the treatment
of metabolic bone diseases, particularly osteopenia and
osteoporosis.63 Intravenous bisphosphonates are prescribed
for patients with life-threatening hypercalcemia caused
by multiple myeloma and breast and prostate cancer.64
There is evidence of a relation between the use of
systemic bisphosphonates and osteonecrosis of the jaw
(ONJ), particularly in those receiving high intravenous
doses, such as cancer patients.65 The risk of bisphosphonate-induced ONJ has led to the recommendation
that these patients not be subjected to any surgical
procedures, including placement of dental implants.64,65
that there was no significant difference between the
incidence of ONJ among patients taking bisphosphonates and the control group. Also, Grant et al.68 found
no significant difference in treatment results between
patients with and without oral bisphosphonates during
implant treatment and no patients developed ONJ after
implant treatment. Finally, after a systematic review,
Madrid and Sanz69 concluded that a patient receiving
oral bisphosphonates for less than 5 years is “safe” to
undergo dental procedures, specifically dental implants.
Several cases report bisphosphonate-induced ONJ
following implant placement.70-74 For instance, Starck and
Epker70 describe a patient who had 5 implants placed in
the lower incisor region followed by successful osseointegration; subsequent use of oral etidronate disodium for
osteoporosis resulted in the displacement of all 5 implants
after 5 months. Wang et al.71 reported the development
of bisphosphonate-induced ONJ in a patient who had
been taking oral bisphosphonates for over 10 years.
Recently, the American Association of Oral and Maxillofacial Surgeons released a position paper75 advocating
the use of the term medication-related ONJ instead of
bisphosphonate-induced ONJ in light of evidence suggesting that other antiresorptive agents, such as antibodies
against receptor activator of nuclear factor κB ligand,
as well as antiangiogenic medications can have effects
similar to those of bisphosphonates. They concluded that
the rate of medication-related ONJ in patients taking oral
antiresorptive medications for more than 3 years can be as
high 0.5% following dental extractions. The position paper
does not comment on the risk of developing medication-related ONJ following placement of dental implants.
In summary, there are insufficient data to suggest
that implant placement should be avoided in
patients receiving bisphosphonates. Nonetheless,
dental practitioners who place implants must to be
aware of the risk of treating patients who are under
bisphosphonate therapy, oral or intravenous.
Chemotherapeutic Agents
However, we found conflicting evidence on the effects
of bisphosphonates on osseointegration. For instance,
Fugazzatto and co-workers66 found that a history of oral
bisphosphonates for 3 years did not lead to ONJ after
implant placement. Similarly, in a parallel-group controlled
trial involving patients who had undergone surgical
placement of dental implants, Jeffcoat67 concluded
Chemotherapy is the use of medications (cytostatic or
cytotoxic agents) that prevent the proliferation of cancer
cells and, ultimately, can cause their destruction.76,77 The
main disadvantage of most chemotherapeutic agents
and antineoplastic drugs is their lack of selectivity. In
addition to targeting fast-growing cancer cells, these
agents also act on normal cells that have an accelerated
cell cycle, such as bone marrow cells, hair follicle cells
and the epithelial cells of the gastrointestinal tract.77 The
detrimental effect of chemotherapy on bone has been
suspected for many years,78 and the chemotherapeu-
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tic agents methotrexate and doxorubicin have been
implicated in the delay of bone healing.79 Moreover,
chemotherapy is known to adversely affect patients’
nutritional status, and there is evidence that poor nutrition
can impair osseointegration and fracture healing.78
Young et al.80 examined the effects of chemotherapy on
bone formation around femoral prostheses by administrating cisplatin to dogs pre- or postoperatively: postoperative
chemotherapy caused less bone formation, while preoperative chemotherapy did not alter the formation of new
bone. With regard to dental implants, Kovacs81 demonstrated successful osseointegration and functional stability
in patients with a history of chemotherapy when implants
were inserted at least 6 months after therapy. Similarly, a
retrospective study by the same investigator concluded that
chemotherapy with cisplatin or carboplatin and 5-fluorouracil was not detrimental to the survival and success of
dental implants in the mandible.82 Other case reports also
show that chemotherapy appears to have no detrimental
effects on implant osseointegration or survival.83,84 Thus, it
seems that there is no substantial evidence in the literature
to prevent a patient who has received chemotherapy from
having a dental implant surgically placed in the mandible
or maxilla. Nonetheless, chemotherapy is one of many
anti-cancer therapies and, as other treatment modalities
may cause detrimental effects in the oral cavity, these must
be considered at the time of implant treatment planning.
THE AUTHORS
Dr. Ouanounou is assistant professor, department of
clinical sciences (pharmacology), faculty of dentistry,
University of Toronto, Toronto, Ontario.
Dr. Hassanpour is perio resident, department of
periodontology, faculty of dentistry, University of Toronto,
Toronto, Ontario.
Dr. Glogauer is professor, faculty of dentistry, University of
Toronto, Toronto, Ontario.
Correspondence to: Dr. Aviv Ouanounou, Dept. of Clinical Sciences,
Pharmacology, Faculty of Dentistry, University of Toronto, 124 Edward
St., Room 513, Toronto ON M5G 1G6. Email: aviv.ouanounou@dentistry.
utoronto.ca
The authors have no declared financial interests.
Conclusion
Implants have been used in dentistry with much success in
the last 3 decades. Optimal bone remodeling, repair and
healing in the early stages of osseointegration are essential
for the ultimate success of these devices. Many factors
that affect bone healing may affect osseointegration
and, thus, may contribute to implant failure. Several drugs
have been shown to impede bone healing. We have
described the effects of CsA, glucocorticoids, alcohol,
SSRIs, NSAIDs, antiresorptives and chemotherapeutic
agents on osseointegration. Although som e studies clearly
show direct effects on osseointegration and thus implant
success, many of these are in vitro or animal studies
and, thus, cannot be applied to humans. We, therefore,
recommend that clinicians be aware of the potential issues
outlined in this paper. Further human studies are needed.
J Can Dent Assoc 2016;82:g7
This article has been peer reviewed.
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